DESCRIPTION: (Applicant's Abstract) Critically ill children in the pediatric intensive care unit often require long-term sedation and analgesia. Fentanyl has a rapid onset, short duration of action, and stable hemodynamic profile. Thus, it is the most desirable opioid for continuous analgesia and sedation in the pediatric intensive care unit. However, continuous administration of fentanyl often leads to rapid development of tolerance, progressive dose escalations, and ultimately iatrogenic opioid dependence. Discontinuation of fentanyl in these children will precipitate acute abstinence syndrome which may compromise the care of the child. Currently, it is not fully understood which patients are at risk for opioid dependence and withdrawal, nor is there a validated method of objectively assessing the severity of withdrawal. Although the optimal treatment of iatrogenic opioid abstinence syndrome has not been established in critically ill children, oral methadone is often used to facilitate fentanyl discontinuation while preventing signs and symptoms of withdrawal. However, no data are available regarding the optimal dose or pharmacokinetics of methadone in this patient population. This proposal aims to generate data on wide ranging aspects of iatrogenic fentanyl dependence, including diagnosis and evaluation of its severity, determination of risk factors for its development, and the pharmacokinetics of fentanyl and methadone in critically ill children. The specific aims of these studies are: 1) to validate a clinical scoring tool to be used by the bedside nurse to objectively measure the severity of iatrogenic fentanyl abstinence syndrome. This scoring tool may be used to determine when treatment of fentanyl withdrawal is necessary; 2) to quantitate fentanyl exposure by measuring fentanyl's cumulative area under the concentration-time curve; 3) to evaluate the relationship between systemic fentanyl exposure and the risk of iatrogenic opioid abstinence syndrome; and 4) to define the pharmacokinetics and bioavailability of methadone which is used to treat fentanyl withdrawal in these critically ill children. These data will significantly augment our understanding of opioid withdrawal in critically ill children and increase our knowledge of fentanyl and methadone pharmacokinetics, both of which are critical in safely administering these agents to children.